Comparison of TAS0953/HM06 and selpercatinib in <i>RET </i>fusion-driven preclinical disease models of intracranial metastases.
Authors: Igor Odintsov, Allan J.W. Lui, Kota Ishizawa, Isao Miyazaki, Inna Khodos, Kentaro Wakayama, Morana Vojnic, Connor J. Hagen, Qing Chang, Annalisa Bonifacio, Claudio Giuliano, Elisa de Stanchina, Emanuela Lovati, Emily Cheng, Marc Ladanyi, Romel Somwar
Journal: Journal of Clinical Oncology (2022)

2024 Background: Patients with RET fusion-positive NSCLC have an estimated 25% incidence of CNS metastasis at diagnosis, and up to 40% during disease progression. Effective anti-RET therapy that penetrates the blood-brain barrier is essential to extending survival. TAS0953/HM06 is a structurally distinct RET-specific inhibitor that exhibits a distinct binding mode to RET and is effective against RET solvent front (G810) and gatekeeper (V804) mutations. TAS0953/HM06 also inhibits growth of xenograft tumors established from RET fusion-driven tumors of multiple histologies. TAS0953/HM06, therefore, represents a potentially effective strategy to overcome the emergence of acquired resistance to first generation RET-selective inhibitors. Here, we compared the brain penetration and efficacy of TAS0953/HM06 to selpercatinib (FDA-approved RET inhibitor) in models of intracranial RET fusion-positive cancers, specifically NSCLC and sarcoma. Methods: We compared the brain: plasma ratio of unbound TAS0953/HM06 and selpercatinib in mice to determine the unbound partition coefficient, Kp uu , brain. We injected ECLC5 (NSCLC cell line, TRIM33-RET) and HMSC-RET (immortalized human mesenchymal stem cells in which SPECCL1-RET was introduced by CRISPR-Cas9 genomic engineering, sarcoma model) cells expressing luciferase into the cerebellum of mice. Tumor-bearing mice were treated with TAS0953/HM06 (50 mg/kg BID), selpercatinib (10 mg/kg BID) or vandetanib (multi-kinase RET inhibitor, 50 mg/kg QD), and assessed weekly for tumor growth via bioluminescence imaging. Results: Kp uu , brain, of TAS0953/HM06 and selpercatinib were 1.3 and 0.20, respectively. Substances with brain Kp uu &gt; 0.3 in mice are regarded as brain-penetrable. TAS0953/HM06 was superior to selpercatinib at inhibiting growth of ECLC5 (p &lt; 0.0001) and HMSC-RET (p = 0.0005) brain xenograft tumors, and increasing survival of tumor-bearing animals (ECLC5: TAS0953/HM06 139±0.5 days, selpercatinib 95+2.3 days, p = 0.002; HMSC-RET: TAS0953/HM06 41± 2.2 days, selpercatinib 20±3 days, p = 0.0001). Vandetanib, which is highly brain-penetrant, did not cause a significant decrease in growth of either brain tumor xenograft models. At the doses used, the 3 RET inhibitors induced similar regression in several peripheral subcutaneous xenograft tumor models. Conclusions: Our data in animal models suggest that TAS0953/HM06 penetrates the CNS more effectively than selpercatinib, and is superior at decreasing CNS disease and extending survival. TAS0953/HM06 represents a promising new therapeutic option for patients with RET fusions with acquired resistance mutations, including those with brain metastasis and those resistant to first-generation selective RET inhibitors. TAS0953/HM06 is currently undergoing a biomarker-driven phase 1/ 2 clinical trial for patients with solid tumors driven by RET alterations (NCT04683250).